rs17075

Variant names:

• chr11-119088621-G-A
• rs17075
• NM_000190.4:c.88-14G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000190.4(HMBS):​c.88-14G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.56 in 1,605,040 control chromosomes in the GnomAD database, including 256,196 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (29024 hom., cov: 31)
  • Exomes 𝑓: 0.55 (227172 hom.)
• Consequence: HMBS NM_000190.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.286
• Publications: 26 publications found

Genes affected

HMBS (HGNC:4982): (hydroxymethylbilane synthase) This gene encodes a member of the hydroxymethylbilane synthase superfamily. The encoded protein is the third enzyme of the heme biosynthetic pathway and catalyzes the head to tail condensation of four porphobilinogen molecules into the linear hydroxymethylbilane. Mutations in this gene are associated with the autosomal dominant disease acute intermittent porphyria. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

HMBS Gene-Disease associations (from GenCC):

• acute intermittent porphyria

  Inheritance: SD, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 11-119088621-G-A is Benign according to our data. Variant chr11-119088621-G-A is described in ClinVar as Benign. ClinVar VariationId is 255487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.745 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000190.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMBS	NM_000190.4	MANE Select	c.88-14G>A		intron	N/A	NP_000181.2
	HMBS	NM_001425056.1		c.88-14G>A		intron	N/A	NP_001411985.1
	HMBS	NM_001425057.1		c.88-14G>A		intron	N/A	NP_001411986.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMBS	ENST00000652429.1	MANE Select	c.88-14G>A		intron	N/A	ENSP00000498786.1
	HMBS	ENST00000392841.1	TSL:1	c.37-14G>A		intron	N/A	ENSP00000376584.1
	HMBS	ENST00000545621.5	TSL:1	n.88-14G>A		intron	N/A	ENSP00000444849.1

Frequencies

GnomAD3 genomes AF: 0.608 AC: 92329 AN: 151916 Hom.: 28992 Cov.: 31

Gnomad AFR AF: 0.752

Gnomad AMI AF: 0.637

Gnomad AMR AF: 0.680

Gnomad ASJ AF: 0.569

Gnomad EAS AF: 0.283

Gnomad SAS AF: 0.501

Gnomad FIN AF: 0.459

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.561

Gnomad OTH AF: 0.604

GnomAD2 exomes AF: 0.560 AC: 140916 AN: 251432 AF XY: 0.552

Gnomad AFR exome AF: 0.752

Gnomad AMR exome AF: 0.725

Gnomad ASJ exome AF: 0.574

Gnomad EAS exome AF: 0.278

Gnomad FIN exome AF: 0.468

Gnomad NFE exome AF: 0.557

Gnomad OTH exome AF: 0.569

GnomAD4 exome AF: 0.555 AC: 805838 AN: 1453006 Hom.: 227172 Cov.: 31 AF XY: 0.553 AC XY: 399884 AN XY: 723366

African (AFR) AF: 0.754 AC: 25126 AN: 33314

American (AMR) AF: 0.720 AC: 32210 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.571 AC: 14892 AN: 26078

East Asian (EAS) AF: 0.268 AC: 10649 AN: 39674

South Asian (SAS) AF: 0.518 AC: 44592 AN: 86136

European-Finnish (FIN) AF: 0.471 AC: 25141 AN: 53414

Middle Eastern (MID) AF: 0.580 AC: 3318 AN: 5724

European-Non Finnish (NFE) AF: 0.558 AC: 616199 AN: 1103856

Other (OTH) AF: 0.561 AC: 33711 AN: 60100

GnomAD4 genome AF: 0.608 AC: 92412 AN: 152034 Hom.: 29024 Cov.: 31 AF XY: 0.602 AC XY: 44729 AN XY: 74302

African (AFR) AF: 0.752 AC: 31176 AN: 41484

American (AMR) AF: 0.679 AC: 10379 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.569 AC: 1977 AN: 3472

East Asian (EAS) AF: 0.283 AC: 1458 AN: 5154

South Asian (SAS) AF: 0.501 AC: 2415 AN: 4822

European-Finnish (FIN) AF: 0.459 AC: 4857 AN: 10576

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.561 AC: 38130 AN: 67944

Other (OTH) AF: 0.603 AC: 1267 AN: 2102

Alfa AF: 0.583 Hom.: 37384

Bravo AF: 0.631

Asia WGS AF: 0.416 AC: 1444 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Acute intermittent porphyria (3)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	6.6
DANN	Benign	0.64
PhyloP100		0.29
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs17075; hg19: chr11-118959331; COSMIC: COSV53828568; COSMIC: COSV53828568;